Stem cells hold great promise for treating many age-related disorders through cell replacement therapy, yet little is known about the ability of aged tissue to support critical events in the survival, spatial targeting, or differentiation of grafted stem cells or primitive progenitor cells. In the central nervous system, an age-related decline in neurogenesis in the dentate gyrus has been reported. We have recently found a massive decline in neurogenesis in the aged olfactory bulb, the other region supporting neurogenesis in the adult brain. Therefore, the environment of the aging brain may be impaired for supporting differentiation and integration of either endogenous or grafted stem cells. In this regard, comparison of aging brain with young brain may provide a useful model to discriminate between critical environmental factors regulating neurogenesis and supporting neuronal differentiation. Identifying such age-related deficits and restoring their expression in the aged brain would be necessary to extend the possible use of cell replacement strategies for treating age-related neurodegeneration, stroke, or cognitive decline. Alternatively, the environment of the aging brain may retain adequate neuronal differentiation signals in these neurogenic regions, but the endogenous stem cells may exhibit age-related impairment in their ability to differentiate. This project will test these two possibilities by 1) evaluating differences in expression of identified stem cell proliferation and differentiation signals between young and aged adult brain and 2) restoring expression of deficient signals by gene delivery to enhance neurogenesis in the aged brain. The subsequent grafting of rodent stem cells derived from embryonic, young adult and aged adult tissue sources will reveal the extent to which environmental modification of aged tissue can facilitate effective cell replacement therapy.